Biology subjects

Jhang, J.

Publications and source records attributed to Jhang, J..

5 recordsLinked to original sources

bioRxiv2026

Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes

Coordination between innate immune signaling and glucose metabolism is fundamental to organismal homeostasis, yet despite decades of study linking immunity and metabolism, the mechanisms by which metabolic cells restrain antiviral innate signaling while preserving glycolytic competence during overnutrition remain poorly defined. Here we identify Tetherin (BST2) as a unique cell-intrinsic immunometabolic checkpoint that couples restraint of type I interferon (IFN-I) signaling to preservation of glycolytic capacity in adipocytes. Tetherin localizes to endoplasmic reticulum and organizes an interactome enriched for antiviral sensing regulators and glycolytic control nodes in adipocytes. Mechanistically, Tetherin directly engages the ubiquitin-dependent degradation machinery NDFIP1 and RNF128 to terminate IRF3 activation, thereby limiting pro-inflammatory, anti-glycolytic signaling and protecting adipocytes from metabolic dysfunction. In parallel, multiomics integration reveals that Tetherin also acts as a scaffold that binds and spatially organizes and activates PFKFB3 to increase glycolytic capacity and restrain MAVS-IRF3 innate immune signalling. In vivo, adipocyte-specific loss of Tetherin amplifies high sucrose diet and high-fat-diet-induced glucose intolerance and liver steatosis, whereas overexpression of human Tetherin in adipocyte suppresses obesity-driven interferon signaling, restores glycolytic pathway, and improves metabolic homeostasis. Orthogonal perturbations in cancer and insulinoma cells further confirm an immunometabolic role for Tetherin. Together, these findings define Tetherin as a dual node immunometabolic checkpoint that couples restraint of antiviral innate inflammatory signaling to maintenance of glycolytic competence, thereby safeguarding adipocyte metabolic homeostasis.

cell biology↗

bioRxiv2024

Encoding opposing valences through frequency-dependent transmitter switching in single peptidergic neurons

Peptidergic neurons often co-express fast transmitters and neuropeptides in separate vesicles with distinct release properties. However, the release dynamics of each transmitter in various contexts have not been fully understood in behaving animals. Here, we demonstrate that calcitonin gene-related peptide (CGRP) neurons in the external lateral subdivision of the parabrachial nucleus (CGRPPBel) encode opposing valence via differential release, rather than corelease, of glutamate and neuropeptides, according to firing rate. Glutamate is released preferentially at lower firing rates with minimal release at higher firing rates, whereas neuropeptides are released at higher firing rates, resulting in frequency-dependent switching of transmitters. Aversive stimuli evoke high frequency responses with accompanying neuropeptide release to encode negative valence, whereas appetitive stimuli evoke low frequency responses with glutamate release to encode positive valence. Our study reveals a previously unknown capability of single CGRPPBel neurons to bidirectionally encode valence via frequency-dependent differential release of transmitters in vivo.

neuroscience↗

bioRxiv2023

A top-down slow breathing circuit that alleviates negative affect

Breathing is profoundly influenced by both behavior and emotion1-4 and is the only physiological parameter that can be volitionally controlled4-6. This indicates the presence of cortical-to-brainstem pathways that directly control brainstem breathing centers, but the neural circuit mechanisms of top-down breathing control remain poorly understood. Here, we identify neurons in the dorsal anterior cingulate cortex (dACC) that project to the pontine reticular nucleus caudalis (PnC) and function to slow breathing rates. Optogenetic activation of this corticopontine pathway (dACC[->]PnC neurons) in mice slows breathing and alleviates behaviors associated with negative emotions without altering valence. Calcium responses of dACC[->]PnC neurons are tightly correlated with changes in breathing patterns entrained by behaviors, such as drinking. Activity is also elevated when mice find relief from an anxiety-provoking environment and slow their breathing pattern. Further, GABAergic inhibitory neurons within the PnC that receive direct input from dACC neurons decrease breathing rate by projecting to pontomedullary breathing centers. They also send collateral projections to anxiety-related structures in the forebrain, thus comprising a neural network that modulates breathing and negative affect in parallel. These analyses greatly expand our understanding of top-down breathing control and reveal circuit-based mechanisms by which slow breathing and anxiety relief are regulated together.

neuroscience↗

bioRxiv2023

Novel genetically encoded tools for imaging or silencing neuropeptide release from presynaptic terminals in vivo

Neurons produce and release neuropeptides to communicate with one another. Despite their profound impact on critical brain functions, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide release in vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects the neuropeptides release presynaptically, and a genetically encoded silencer that specifically degrades neuropeptides inside the LDCV. Monitoring and silencing peptidergic and glutamatergic transmissions from presynaptic terminals using our newly developed tools and existing genetic tools, respectively, reveal that neuropeptides, not glutamate, are the primary transmitter in encoding unconditioned stimulus during Pavlovian threat learning. These results show that our sensor and silencer for peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake behaving animals.

neuroscience↗

bioRxiv2020

Identification of a novel breathing circuit that controls pain and anxiety

Alleviating pain with controlled breathing has been practiced throughout human history. Despite its wide use and long history, a neural circuit-based understanding of the pain-breathing interaction is largely lacking. Here we report a novel breathing circuit that regulates non-homeostatic breathing rhythm, as well as pain and anxiety. We identify that a cluster of neurons expressing the Oprm1 gene, which encodes the -opioid receptor (MOR) in the lateral subdivision of parabrachial nucleus (PBLOprm1), directly regulates breathing rate in mice by conveying signals from the limbic areas to respiratory rhythm generating neurons in the medullary preBotzinger Complex (preBotC). In addition, we found that pain signals rapidly increase breathing rate by activating these neurons in both awake and anesthetized mice. Inactivating these neurons not only decreases the breathing rate, but it also substantially decreases anxiety-like behaviors and induces strong appetitive behaviors. Furthermore, PBLOprm1 inactivation alleviates pain by attenuating the perception of the affective-motivational aspect of pain. These results suggest that PBLOprm1 neurons play a critical role in the non-homeostatic regulation of breathing and in the regulation of pain and anxiety through breathing.

neuroscience↗